The kappa-opioid receptor (KOR) is encoded by the OPRK1 gene and is a member of the opioid receptor family which binds the opioid peptide dynorphin as the primary endogenous ligand. The KOR has a wide, yet distinct distribution in the brain, spinal cord, and in peripheral tissues, and particularly in brain areas implicated in reward, cognitive function and stress responsiveness. Evidence indicates that dynorphins are elevated under painful and stressful conditions, and that KOR disruption produces anti-stress effects. Such findings have led to development of KOR antagonists for treatment of depressive, anxiety, addictive disorders, as well as other psychiatric conditions associated with stress. Development of KOR antagonists is summarized in the article entitled “Antagonists of the Kappa Opioid Receptor” by Urbano et al., Bioorganic & Medicinal Chemistry Letters, 24:2021-2032, 2014.
Pharmacological studies with prototypical KOR antagonists (i.e., the morphinan-derived ligands nor-BNI and GNTI, and the non-morphinan JDTic), have confirmed the therapeutic potential of the KOR/dynorphin system. However, such prototypical KOR antagonists display delayed onset of action in the range of hours to days, followed by antagonism effects lasting weeks at minimally effective doses. Furthermore, such compounds showed poor blood-brain barrier penetration. Thus, more recent research has focused on the development of short-acting KOR antagonists with improved pharmacokinetics.
KOR antagonists have been extensively studied because they block a prominent stress-induced neuroadaptation; namely, elevated expression of dynorphin in the nucleus accumbens (NAc). The NAc is an element of the mesolimbic system which plays a role in motivation and the pathology of psychiatric disorders. Stress, as well as repeated exposure to drugs of abuse, triggers a complex sequence of intracellular events involving the transcription factor CREB, a cAMP response element binding protein, in the NAc. As explained by Carlezon et al. in “Kappa Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials” (Depression and Anxiety, 33:895-906, 2016), CREB-mediated increases in the expression of dynorphin produce depressive-like signs, which KOR antagonists mitigate. According to the model set forth by Carlezon et al., stress activates CREB in the NAc, which leads to an increase in dynorphin expression. Increased dynorphin, in turn, promotes activation of KORs. KORs are expressed on the cell bodies and terminals of mesocorticolimbic dopamine (DA) neurons and activation of KORs inhibit DA release. Treatment with a KOR antagonist blocks the action of dynorphin, restoring DA function, and thereby providing antidepressant- and anxiolytic-like effects in various animal models.
Such mechanisms of action, as well as the rather extensive development and testing of KOR antagonists to date, including recent clinical study results (e.g., CERC-501 and ALKS-5461), provide strong evidence that KOR antagonists may have therapeutic effects in humans suffering from a wide range of disorders, including mood disorders, anxiety disorders and substance use disorders as defined, for example, in the Diagnostic and Statistical Manual of Mental Disorder (DSM). Another framework for classifying psychopathology disorders is the Research Domain Criteria (RDoC) project, which aims to classify such disorders based on dimensions of observable behavior and neurobiological dimensions. In this context, KOR antagonists have therapeutic effect on at least two types of RDoC-defined domains; namely, those related to reward and those related to adverse effects of stress. Within these domains, use of KOR antagonists for treatment of anhedonia (“positive valence system”), and for blocking the adverse effects of stress (“negative valence system”), have been recognized.
As a result of the advances made in this field, KOR antagonists are recognized for their utility in treating major depression and disorders related to substance abuse or addiction, particularly in the context of rapidly acting treatments which avoid the drawbacks associated with the prototypical KOR antagonists discussed above. Other studies have shown that KOR antagonists may be particularly useful for the treatment of stress-mediated symptoms, as well as for treating social anxiety disorder and phobias. Prophylactic therapy has also been suggested to prevent adverse conditions arising from stress, and in this regard KOR antagonism has been proposed as a preventative treatment of PTSD in individuals at risk of the same. Other therapeutic applications of KOR antagonism include the treatment of impairment in reward-related function as it frequently occurs in patients with mood and anxiety spectrum disorders, and which may also occur with other types of conditions such as schizophrenia or a schizoaffective disorder.
In summary, KOR antagonism provides significant promise for the treatment of a wide variety of disorders and conditions. As a result, a number of compounds are currently in development that are highly selective and potent KOR antagonists for treating a variety of conditions, such as substance use disorders, major depression, anhedonia, and stress-related symptoms. However, and despite the advances made in this field, there remains a need for new and improved KOR antagonists, as well as for pharmaceutical products containing the same, and for methods related to their use and manufacture.